High-performance liquid chromatographic method for the separation of the optical isomers of γ,γ′-di-tert.-butyl- -γ-carboxyglutamic acid and -γ-carboxyglutamic acid

The chemical synthesis of γ,γ′-tert.-butyl-γ-carboxyglutamic acid is accompanied by extensive racemization, and very careful resolution is needed to obtain and -γ,γ′-di-tert.-butyl-γ-carboxyglutamic acids in high chiral purity. A novel method was devised for the separation of enantiomers of γ,γ′-di-tert.-butyl-γ-carboxyglutamic acid and γ-carboxyglutamic acid, applying precolumn derivatization with 1-fluoro-2,4-dinitrophenyl-5- -alanine amide and 2,3,4,6-tetra-O-acetyl-β- -glucopyranosyl isothiocyanate as chiral reagents, with subsequent reversed-phase high-performance liquid chromatographic separation of diastereomeric compounds. The effects of organic modifiers, of the mobile-phase composition and of the pH on the separation of the diastereomers were investigated.     

Synthesis of L-α-aminoadipyl-L-serinyl-D-valine,a naturally occuring tripeptide from the fermentation of Penicillium chrysogenum

A new tripeptide, L -α-aminoadipyl-L -seryl-D-valine has been synthesized by coupling the protected L-seryl-D -valine dipeptide with an appropriately protected L -α-aminoadipic acid ester. The free tripeptide was obtained after treatment with liquid HF and purification by HPLC.     

Stereoselective synthesis of D-α-glucopyranosides,di-and tri-saccharides via 6-O-acetyl-glucopyranosyl bromides

Acetyl bromide cleaved 2,3,4-tri-O-benzyl-l,6-anhydro-B-D-glucopyranose (la) or 2,3,4-tri-O-benzyl-1,6-anhydro-B-Z)-galactopyranose (1a') to give the corresponding a-D-pyranosyl bromides (2). Reaction of 2 with ROH/diisopropylethylamine gave the corresponding a-glucopyra-nosides, di- and tri-saccharides with good yield. It was available to use 13C NMR to monitor the glycosidation reaction.     

Graft copolymers containing nucleic acid bases and L-α-amino acids

Graft copolymers of nucleic acid bases and L-α-amino acids on polyethyleneimine were synthesized, and carboxyl derivatives of adenine and thymine were grafted by the p-nitrophenyl ester method onto linear and branched polyethyleneimine. The carboxyl derivatives of nucleic acid bases were also grafted onto the monomeric graft copolymers of L -α-amino acids on polyethyleneimine; the carboxyl derivatives were obtained by the condensation of polyethyleneimine with L -α-amino acids with a coupling agent.     

β-Thiopeptides: Synthesis,NMR Solution Structure,CD Spectra,and Photochemistry

To test the effect of NH−C=S groups (Scheme 1) on the stability of β-peptide secondary structures, we have synthesized three β-thiohexapeptide analogues of H-(β-HVal-β-HAla-β-HLeu)₂-OH ( 1 ) with one, two, and three C=S groups in the N-terminal positions (cf. 2 – 4 and model in Fig. 1). The first C=S group was introduced selectively by treatment with Lawesson reagent of Boc-β-dipeptide esters ( 6 and 8 ). A series of fragment-coupling steps (with reagents as for the corresponding sulfur-free building blocks) and another thionation reaction led to the title compounds with a C=S group in residues 1, 1, and 3, as well as 1, 2, and 3 of the β-hexapeptide (Schemes 2 and 3). The sulfur derivatives, especially those with three C=S groups, were much more soluble in organic media than the sulfur-free analogues (>1000-fold in CHCl₃; Table 1). The UV and CD spectra (in CHCl₃, MeOH, and H₂O) of the new compounds were recorded and compared with those of the parent β-hexapeptide 1 (Figs. 2 – 4); they indicate the presence of more than one secondary structure under the various conditions. Most striking is a pronounced exciton splitting (Δλ ca. 20 nm, amplitude up to +121000) of the ππ*_C=S band near 270 nm with the β-trithiohexapeptide (with and without terminal protecting groups), and strong, so-called `primary solvent effects', in the CD spectra. The CD spectrum of the β-dithiohexapeptide 3 undergoes drastic changes upon irradiation with 266-nm laser light of a MeOH solution (Fig. 5). The NMR structure in CD₃OH of the unprotected β-trithiohexapeptide 4 was determined to be an (M)-3₁₄-helix (Fig. 7), very similar to that of the non-thionated analogue (cf. 1 ). NMR and mass spectra of the β-hexapeptides with C=S and with C=O groups are compared (Figs. 6 and 8).     

Synthesis and characterization of poly-β-hydroxybutyrate. I. Synthesis of crystalline DL-poly-β-hydroxybutyrate from DL-β-butyrolactone

The polymerization of β-butyrolactone was investigated as a possible monomer for a proposed synthesis of the naturally occurring polyester, D -poly-β-hydroxybutyrate (D -PHB). The racemic DL -monomer was used in this initial study to determine the best conditions and catalyst system for use in a subsequent study of the polymerization of optically active β-butyrolactone. In so doing it was found that certain organometallic catalysts (Et₂Zn and Et₃Al) plus a cocatalyst of water produced highly crystalline samples of polyester from the racemic monomer. This paper describes the synthesis and characterization of the racemic polymer obtained using these catalyst systems, and compares the results obtained with certain other catalysts that were also investigated for this purpose. Examination of the DL -PHB by infrared, NMR, x-ray, and electron microscopy shows that it is possible to synthesize a crystalline racemic polymer that is virtually identical (excepting optical activity) to the naturally occurring polymer, D -PHB.     

ε-Aminocaproylcholine: Chemical Synthesis,Biological Properties,and Interactions with Receptor Molecules

ε-Aminocaproylcholine, [¹⁴CH₃-]ε-aminocaproylcholine, and their Sepharose-2B derivatives ( 6 ) were synthesized. ε-Aminocaproylcholine is a full cholinergic agonist (nicotinic) with a potency intermediate between that of acetylcholine and of carbachol. ε-Aminocaproylcholine is not hydrolysed by acetylcholine esterase, but is an inhibitor. Its Sepharose-2B derivatives are shown to be effective affinity-chromatographic agents for the isolation of acetylcholine-binding proteins (receptors).     

Synthesis of γγγ-trifluorocarbonyl compounds

γγγ-Trifluorocarbonyl compounds are easily obtained in a good yield by introduction of the 1,1,1-trifluoroethyl moiety (CF₃-CH₂-) on the -methylene group of a ketone.     

Synthesis of Mono-Amino Substituted γ-CD: Host–Guest Complexation and In Vitro Cytotoxicity Investigation

Cyclodextrins (CDs) are cyclic oligosaccharides which can trap hydrophobic molecules and improve their chemical, physical, and biological properties. γ-CD showed the highest aqueous solubility with the largest cavity diameter among other CD types. The current study describes a direct and easy method for nucleophilic mono-aminos to be substituted with γ-CD and tested for their ability to host the guest curcumin (CUR) as a hydrophobic drug model. The mass spectrometry and NMR analyses showed the successful synthesis of three amino-modified γ-CDs: mono-6-amino-6-deoxy-cyclodextrine (γ-CD-NH₂), mono-6-deoxy-6-ethanolamine-γ-cyclodextrine (γ-CD-NHCH₂CH₂OH), and mono-6-deoxy-6-aminoethylamino)-γ-cyclodextrin (γ-CD-NHCH₂CH₂NH₂). These three amino-modified γ-CDs were proven to be able to host CUR as native γ-CDs with formation constants equal to 6.70 ± 1.02, 5.85 ± 0.80, and 8.98 ± 0.90 mM⁻¹, respectively. Moreover, these amino-modified γ-CDs showed no significant toxicity against human dermal fibroblast cells. In conclusion, the current work describes a mono-substitution of amino-modified γ-CDs that can still host guests and showed low toxicity in human dermal fibroblasts cells. Therefore, the amino-modified γ-CDs can be used as a carrier host and be conjugated with a wide range of molecules for different biomedical applications, especially for active loading methods.     

Synthesis of α‐Cyclodextrin‐Conjugated Poly(ε‐lysine)s and Their Inclusion Complexation Behavior

Novel functional polymers utilizing specific host/guest interactions were designed by introducing α‐CD host molecules into poly(ε‐lysine) chains as side groups. An interesting phase separation was observed as a result of the inclusion complexation between the polymeric host and 3‐(trimethylsilyl)propionic acid as a model guest in aqueous media. This water‐soluble polymeric host would be useful for various applications, particularly drug delivery, due to its biodegradability, low toxicity, and unique functionality represented as a complexation‐induced phase separation.     

Syntheses of the Enantiomers of γ-Cyclogeranic Acid, γ-Cyclocitral,and γ-Damascone: Enantioselective protonation of enolates

(R)-and (S)-γ-cyclogeranic acid ((R)-and (S)- 9 , resp.) were obtained by resolution of the racemate, and their absolute configurations determined by chemical correlation. The γ-acids (R)-and (S)- 9 were converted into (R)-and (S)-methyl γ-cyclogeranate ((R)-and (S)- 6 , resp.), and (R)-and (S)-γ-damascone ((R)-and (S)- 5 , resp.). A more direct entry to (R)-and (S)- 9 consisted in the enantioselective protonation of a thiol ester enolate with (?)- or (γ)-N-isopropylephedrine((?)- or (γ)- 20 ) and subsequent hydrolysis of the (R)-and (S)-S-phenyl γ-thiocyclogeranate ((R)- and (S)- 24 , resp.; 97% ee). The esters (R)- and (S)- 24 were also used as precursors of (R)- and (S)-γ-damascone ((R)- and (S)- 5 , resp.). Alternatively, (S)- 5 (75% ee) was obtained by enantioselective protonation of ketone enolate 29 with (?)-N-isopropylephedrine ((?)- 20 ). Organoleptic evaluation demonstrated that the (S)-enantiomers of methyl γ-cyclogeranate and γ-damascone are markedly superior to their (R)-enantiomers.